During chronic infections such as those caused by HIV-1, hepatitis C virus, and lymphocytic choriomeningitis virus, as well as during tumor outgrowth, antigen-specific CD8 T cells often progressively lose function in a step-wise manner. This loss of functional capacity, termed T cell exhaustion, represents an extreme state of differentiation which is characterized by an inability to elaborate key anti-viral effector activites and, in severe cases, culminates in deletion of the CD8 T cells. Defining how and why exhaustion develops, as well as determining the regulatory mechanisms that maintain this state, are significant as this may permit the development of new strategies to enhance immunity to infections which are difficult to control. This exploratory proposal is built on a foundation of preliminary data from acute infection studies showing that if ICAM-1 is not expressed, then there is greatly enhanced retention of virus-specific effector phenotype CD8 T cells well into the memory phase, even though the infection is cleared. This is significant as preserving this population during chronic viral infections may impede the development of exhaustion and favor viral control. Nevertheless, virtually no information is available regarding the roles of adhesion molecules in dictating the development of T cell exhaustion. Since continuous antigenic activation is required to develop and sustain exhaustion, it is plausible that adhesion molecule interactions amplify the strength of the antigen-dependent signals that the virus-specific CD8 T cell receives, driving the development of exhaustion. This concept, that ICAM-1 interactions influence the differentiation state of the responding T cells, is supported by our preliminary findings. Based upon these findings, as well as published studies of exhausted CD8 T cells, we have formulated the hypothesis that ICAM-1 interactions enhance antigenic signals, and potentiate the development and maintenance of CD8 T cell exhaustion. Testing this hypothesis will provide novel information regarding how T cell exhaustion is controlled and will also determine whether targeting adhesion molecule interactions is a viable therapeutic option during chronic infections. Our specific aims are: (1) Define the requirements for ICAM-1 and LFA-1 in the development of CD8 T cell exhaustion; and (2) Determine whether targeting ICAM-1 interactions is a viable therapeutic option. Completion of the aims of this exploratory proposal will provide novel mechanistic insights into the roles of adhesion molecules in driving and sustaining CD8 T cell exhaustion, and this information may broadly impact our understanding of how CD8 T cell differentiation is corrupted under conditions of chronic antigenic activation, as well as identify potential new therapeutic approaches. PUBLIC HEALTH RELEVANCE: Globally there are over 500 million citizens living with chronic HIV, hepatitis C, or hepatitis B virus infections. The purpose of this proposal is to provide new information regarding why the hosts' defense system is unable to clear these types of infections and investigate a possible new therapeutic option for rejuvenating poorly protective responses.